Project Summary/Abstract Chronic obstructive pulmonary disease (COPD) is a disease characterized by progressive loss of lung function and is the third leading cause of death in the US. Treatments that target the mechanisms underlying COPD pathogenesis do not currently exist and present a logical avenue for new therapeutic development. Our group and others have established that tobacco smoke, the leading cause of COPD, alters the function of the cystic fibrosis transmembrane conductance regulator (CFTR), and that this ?acquired CFTR dysfunction? is also present in COPD. Genetic mutation of this ion channel is responsible for the etiology of cystic fibrosis (CF) which, like COPD, is characterized by progressive reduction in lung function due to defective mucus clearance. The FDA has identified several harmful toxicants in tobacco smoke, among which are reactive aldehydes such as acrolein, which we have shown in preliminary data are detrimental to both CFTR function and mucus clearance. Through the proposed studies, we will elucidate how specific chemicals within tobacco smoke alter CFTR function and mucus clearance in COPD. We hypothesize that acrolein and other aldehydes are principal components of tobacco smoke that inhibit CFTR function and contribute to defective mucus clearance, and that aldehyde scavengers can ameliorate these effects. To test this, we have developed three Specific Aims. In Aim 1, we will characterize how whole cigarette smoke affects CFTR-dependent ion transport and mucus clearance. In Aim 2, we will establish whether reactive aldehydes such as acrolein can recapitulate the effects of whole cigarette smoke in vitro and in vivo. In Aim 3, we will determine whether acrolein blockade using reactive aldehyde scavengers can protect against smoke-induced CFTR dysfunction and subsequent impairment of mucus clearance. These studies will advance the field by revealing the mechanistic basis underlying how tobacco smoke contributes to COPD manifestations, potentially leading to new targets and an innovative treatment approach.